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Na[BH(pz)(3)] and Na[AuCl(4)].2H(2)O react in water (1:1) to give [Au[kappa(2)-N,N'-BH(pz)(3)]Cl(2)] (1) or, in the presence of NaClO(4) (2:1:1), the cationic complex [Au[kappa(2)-N,N'-BH(pz)(3)](2)]ClO(4) (2). The reactions of Na[B(pz)(4)] with the cyclometalated gold complexes [AuRCl(2)] and NaClO(4) (1:1:1) produce [Au[kappa(2)-N,N'-B(pz)(4)](R)]ClO(4) [R = kappa(2)-C,N-C(6)H(4)CH(2)NMe(2)-2 (3)] or [Au[kappa(2)-N,N'-B(pz)(4)](R)Cl] [R = C(6)H(3)(N=NC(6)H(4)Me-4')-2-Me-5 (4)], respectively, although 4 is better obtained in the absence of NaClO(4). The crystal structures of 1 and 3.CHCl(3) are reported. Both complexes display the gold center in square planar environments, two coordination sites being occupied by the chelating poly(pyrazolyl)borate ligands.
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In the title compound, C19H16ClN5O2, the molecules are linked into chains of edge-fused rings by a combination of two independent C-H...O hydrogen bonds, augmented by a centrosymmetric pi-pi stacking interaction.
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Pyrazole is known to interact with and to induce cytochrome P-450 IIE1. Since pyrazole is oxidized by rat liver microsomes to 4-hydroxypyrazole, and several of the actions of pyrazole have been ascribed to its metabolite, experiments were conducted to evaluate the interactions of 4-hydroxypyrazole with microsomes, and to compare these to pyrazole itself. Rats were injected with doses of 4-hydroxypyrazole ranging from 2 to 100 mg/kg body weight/day for 2 days. A slight increase of total cytochrome P-450 was observed at low doses, followed by a decrease at higher concentrations. NADPH-cytochrome P-450 reductase activity was not affected. The oxidation of aniline or dimethylnitrosamine was increased about 50% by the 4-hydroxypyrazole treatment; however, this extent of increase was much less than that produced by pyrazole treatment. In vitro, 4-hydroxypyrazole produced a type II binding spectrum with microsomes, with a peak at about 425 nm and a trough at about 395 nm. The affinity for 4-hydroxypyrazole was increased from a value of about 0.60 mM in control microsomes to a value of about 0.40 mM in microsomes from pyrazole-treated rats. These values are 2-fold greater than those observed with pyrazole as the ligand. 4-Hydroxypyrazole inhibited the microsomal oxidation of ethanol; kinetics of inhibition were mixed. The apparent KI for 4-hydroxypyrazole inhibition of ethanol oxidation by microsomes was about 4 mM, which is about an order of magnitude greater than that for pyrazole. The in vivo and in vitro interactions of 4-hydroxypyrazole with microsomes appear to be similar to those described for pyrazole; however, these interactions are considerably less effective than those of the parent drug, pyrazole. Thus, although some actions of pyrazole may be due to the metabolite 4-hydroxypyrazole, it appears that the induction of P-450 IIE1 and the in vitro interactions of pyrazole with microsomes is not likely to be mediated by prior metabolism of pyrazole to 4-hydroxypyrazole.
Rat liver microsomes oxidize pyrazole to 4-hydroxypyrazole and this oxidation is increased in microsomes isolated from rats treated with inducers of cytochrome P-450 IIE1, such as pyrazole or ethanol. A reconstituted system containing the P-450 IIE1, purified from pyrazole-treated rats, oxidized pyrazole to 4-hydroxypyrazole in a time- and P-450-dependent manner. Oxidation of pyrazole was dependent on the concentration of pyrazole over the range of 0.15 mM to 1.0 mM. In isolated microsomes, glycerol inhibited pyrazole oxidation by about 50% under concentration conditions which occur in the reconstituted system; hence, the values for pyrazole oxidation by the reconstituted systems are underestimated because of the presence of glycerol. Oxidation of pyrazole was inhibited by competitive substrates for P-450 IIE1, such as 4-methylpyrazole, aniline and ethanol, as well as by an antibody raised against the pyrazole-induced P-450 IIE1. Thus, pyrazole is an effective substrate for oxidation by purified P-450 IIE1, extending the substrate specificity of this isozyme to potent inhibitors of alcohol dehydrogenase.
Pyrazole is oxidized to 4-hydroxypyrazole by rat liver microsomes in a cytochrome P-450-dependent reaction and this oxidation can be increased by prior treatment of rats with pyrazole, 4-methylpyrazole, or chronic ethanol feeding. The induction pattern suggests that pyrazole may be an effective substrate for oxidation by P-450 IIE.1. This P-450 isozyme is recognized by antibody (anti-3a IgG) raised against the ethanol-inducible P-450 in rabbits. Experiments were carried out to evaluate the ability of anti-3a IgG to inhibit pyrazole oxidation by microsomes from controls and from rats treated with inducers of P-450 IIE.1. Immunoblots with anti-3a IgG or with the anti-pyrazole P-450 IgG were identical and indicated increased staining of the pyrazole P-450 with microsomes from rats treated with pyrazole, 4-methylpyrazole, or ethanol, relative to saline controls; very little staining occurred with microsomes from pair-fed controls or phenobarbital-treated rats. Rates of pyrazole oxidation were highest with microsomes from rats treated with the inducers of P-450 IIE.1 and lowest with pair-fed controls or rats treated with phenobarbital. Anti-3a IgG produced about a 60% decrease of pyrazole oxidation in microsomes from rats treated with inducers of P-450 IIE.1 and about a 25% decrease with the saline controls; no inhibition was found with microsomes from the phenobarbital-treated rats. The anti-3a IgG-resistant rate of pyrazole oxidation was similar with all the microsomal preparations, and was not due to interaction of pyrazole with hydroxyl radicals.(ABSTRACT TRUNCATED AT 250 WORDS)